Distinct thresholds govern Myc's biological output in vivo.
Distinct thresholds govern Myc's biological output in vivo.
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DOI：
10.1016/j.ccr.2008.10.018
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发表时间：
2008-12-09
期刊：
影响因子：
50.3
通讯作者：
Evan GI
中科院分区：
文献类型：
--
作者：
Murphy DJ;Junttila MR;Pouyet L;Karnezis A;Shchors K;Bui DA;Brown-Swigart L;Johnson L;Evan GI
Myc的失调触发了多种内在的肿瘤抑制程序，这些程序用于抑制Myc的致癌潜力。由于正常细胞增殖也需要Myc活性，因此只有当Myc信号传导是致癌的时，才必须触发内源性肿瘤抑制的激活。然而，细胞如何区分正常和致癌的Myc是未知的。在这里，我们表明，不同的阈值水平的Myc控制其在体内的输出：低水平的失调Myc有能力驱动异位增殖的体细胞和肿瘤发生，但激活的凋亡和ARF/p53内在的肿瘤监视途径需要Myc过表达。需要保持激活的癌基因在低水平，以避免从事肿瘤抑制可能是一个重要的选择压力，控制肿瘤微进化的早期阶段。癌症是通过激活内在的肿瘤抑制程序来预防的，这些程序要么修复细胞中的损伤，要么确保受损细胞不能繁殖。只有当这些肿瘤抑制途径被废除时，癌症才会出现。重要的是，这种肿瘤抑制途径的激活必须仅受致癌而非正常生长信号的限制。使用一种新的Myc诱导的肿瘤发生的体内模型，其中Myc功能失调而没有伴随的过度表达，我们表明肿瘤监视程序是由Myc过度表达而不是失调特异性触发的。尽管如此，低水平的去调节的Myc仍然具有潜在的致癌性。这些观察结果确定了一种新的机制，通过这种机制可以绕过肿瘤抑制防御机制，这对我们理解早期肿瘤具有重要意义。
Deregulated Myc triggers a variety of intrinsic tumor suppressor programs that serve to restrain Myc’s oncogenic potential. Since Myc activity is also required for normal cell proliferation, activation of intrinsic tumor suppression must be triggered only when Myc signaling is oncogenic. However, how cells discriminate between normal and oncogenic Myc is unknown. Here we show that distinct threshold levels of Myc govern its output in vivo: low levels of deregulated Myc are competent to drive ectopic proliferation of somatic cells and oncogenesis but activation of the apoptotic and ARF/p53 intrinsic tumor surveillance pathways requires Myc over-expression. The requirement to keep activated oncogenes at low level to avoid engaging tumor suppression is likely an important selective pressure governing the early stages of tumor microevolution. SIGNIFICANCE Cancers are prevented by the activation of intrinsic tumor suppression programs that either fix the damage in cells or ensure that the damaged cells cannot propagate. Cancers can only arise once these tumor suppressor pathways are abrogated. Importantly, activation of such tumor suppressor pathways must be restricted only by oncogenic, not normal, growth signals. Using a novel in vivo model of Myc-induced tumorigenesis in which Myc function is deregulated without concomitant over-expression, we show that tumor surveillance programs are triggered specifically by Myc over-expression, not deregulation. Nonetheless, low-level deregulated Myc remains potently oncogenic. These observations identify a novel mechanism by which the tumor suppressor defense mechanisms can be circumvented, with implications for our understanding of early stage neoplasia.
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影响因子：
14.9
作者：
Indra, AK;Warot, X;Metzger, D
通讯作者：
Metzger, D
DOI：
10.1073/pnas.92.18.8488
发表时间：
1995-08-29
影响因子：
11.1
作者：
CHIN, L;SCHREIBERAGUS, N;DEPINHO, RA
通讯作者：
DEPINHO, RA
影响因子：
50.3
作者：
Finch, Andrew;Prescott, Julia;Evan, Gerard I.
通讯作者：
Evan, Gerard I.
影响因子：
14.9
作者：
LITTLEWOOD, TD;HANCOCK, DC;EVEN, GI
通讯作者：
EVEN, GI
影响因子：
5.3
作者：
Flinn, EM;Busch, CMC;Wright, APH
通讯作者：
Wright, APH